In the course of the last few decades various pharmacological approaches have been developed for the pharmacological treatment of gastric hyperacidity, a condition which, if present to a marked degree and for prolonged periods, can give rise to various complications or pathologies such as peptic ulcer and gastroesophageal reflux disease.
Among the drugs most widely used are those based on active principles capable of inhibiting inhibitors of the histamine receptor H2 such as, for example, cimetidine, famotidine, nizatidine, ranitidine, or based on active principles capable of inhibiting prostaglandins such as, for example, misoprostol. Another category of drugs is based on active principles which perform the function of protectors of the gastric mucosa such as, for example, bismuth salts, sucralfate or antimuscarinic or parasympatholytic drugs based on pirenzepine and pipenzolate. Finally there are also antacids such as, for example, sodium bicarbonate, aluminium hydroxide or magnesium hydroxide and proton pump inhibitors based on Lansoprazole, Esometazole, Rabeprazole, Pantoprazole and Omeprazole.
Proton pump inhibitors (PPI) are a group of molecules whose principal action consists in a pronounced reduction in the acidity of the gastric juices for a fairly long period of time (18 to 24 hours).
The group containing PPIs is the successor to H2 antihistamines, and PPI inhibitors are broadly more widespread than the latter because of their greater effectiveness.
The medicines mentioned above are used in the symptomatic and aetiological treatment of various syndromes, such as: (i) dyspepsia; (ii) gastro-duodenal ulcer. PPIs are used for treating or preventing gastric and duodenal ulcers. They are also used in association with certain antibiotics in the treatment of gastritis from Helicobacter pylori; (iii) Zollinger-Ellison syndrome and (iv) gastroesophageal reflux disease.
PPIs are also used in patients treated long-term with acetylsalicylic acid or other NSAIDs. By inhibiting the function of the enzyme cyclooxigenase 1 (COX 1), these drugs have the side effect of reducing the synthesis of prostaglandin, a process which depends on the same enzyme. Since one of the functions of prostaglandin is the protection of the gastric mucosa from acidity, PPIs are used in order to reduce acidity and protect the gastric mucosa.
This type of medicine inhibits the gastric enzyme H+/K+-ATPase (the proton pump), catalyst of the H+ and K− ion exchange. This creates effective inhibition of acid secretion.
In the micro-channel where the pH is low, close to 2, these inhibitors are ionised and transformed into molecules capable of establishing covalent bonds with the cysteine thiol group (SH) of the pump sub-unit. The pump is thus irreversibly inhibited. Renewal of pumping activity requires the production of new pumps, an event which requires 18 to 24 hours on average. A single dose of PPI, therefore, enables inhibition of the gastric secretion of about 24 hours.
The fact that the inhibitors are active only in an acid environment explains how they have a minimal effect on the extra-gastric H+/K+-ATPase situated at the level of the rectum and the colon.
In any case, apart from the specific action mechanism, the final effect of almost the totality of these classes of drugs for the treatment of gastric hyperacidity, or other pathological conditions mentioned above, is the raising of the gastric pH according to kinetics and intensities dependent on the specific molecule taken and its dosage. One exception, in this sense, is the prostaglandins and protector drugs for the gastric mucosa which, instead of reducing the intraluminal hydrogen ion concentration, increase the synthesis of mucus and bicarbonate ion by the cells of the gastric wall, thus increasing the protection of the mucosa against acidity of the lumen. In any case, drugs capable of reducing gastric hyperacidity constitute the treatment of choice in cases of peptic ulcer or gastroesophageal reflux, while mucosal protectants represent a complementary therapy.
It is known, furthermore, that normal gastric acidity constitutes an effective barrier against potential harmful organisms or pathogens ingested with the normal diet. Many of them, in fact, are particularly sensitive to acidity and are not capable of surviving for more than five minutes, sometimes even less, at pH values below 3. It follows that many pathogens, among them those belonging to the genus Salmonella, do not reach the intestine alive and, setting aside harmful effects on the human organism mediated by any toxins secreted and already present in food, are not capable of giving rise to an intestinal infection and, therefore, to full-blown food poisoning.
It has to be said, however, that raising the gastric pH values typically found in patients who take drugs to reduce or treat gastric hyperacidity makes these patients more exposed to dietary toxic infections caused especially by consumption of raw food, particularly fish, meat and eggs.
Patients who take drugs to reduce or treat gastric hyperacidity, such as proton pump inhibitors for example, have a stomach pH value of around 5.
This pH value allows Enterobacteriaceae, and particular strains of E. Coli with pronounced decarboxylasic action, to pass through the degraded gastric barrier. Proteins ingested during eating are enzymatically degraded to amino acids which, in the presence of decarboxylasic action, are modified into a series of biogenic amines ranging from potentially dangerous to highly dangerous such as for example histamine, tyramine, putrescine and cadaverine. The most common symptoms which can cause these biogenic amines have a complete overlap with the secondary effects caused by the use of proton pump inhibitors (PPIs), and are as follows: diarrhea, headache, nausea, abdominal pains and flatulence. When certain biogenic amines then react with nitrites, we have the formation of N-nitrosamines. These nitrosamines cause a genetic mutation through alkylation of the DNA, and their presence is associated with cancer of the stomach, the intestine, the pancreas and the bladder, and also with leukaemia.
One possible solution for these patients does not, obviously consist of suspension of the pharmacological treatment because this would expose the gastric or oesophageal mucosa once again to the harmful effects mediated by the gastric juices. On the other hand it is not even thinkable to continue the pharmacological treatment and leave the patients exposed to these risks of infection.
There remains, therefore, a need to allow patients in need, on the one hand, to take drugs for reducing or treating gastric hyperacidity and, on the other hand, to avoid being exposed to highly dangerous pathogenic infections or to risks of recurrent pathogenic infections.
In particular, it remains necessary to be able to respond to the above-mentioned needs by means of a composition of natural origin, free of side-effects, with an improved and selective antimicrobial efficacy against pathogens, such as for example coliforms which are a group of bacteria belonging to the family of Enterobacteriaceae and which includes, among others, Citrobacter, Enterobacter, preferably Enterobacter cloacae, Escherichia, preferably E. coli, including serotype O157:H7, Hafnia, Klebsiella, preferably Klebsiella pneumoniae, Serratia and Yersinia, or other pathogens such as the Clostridiaceae, including Clostridium difficile, Salmonella enteriditis, Campylobacter jejuni and Helicobacter pylori. 